Esters of retinoic acid and azetidinone derivatives

ABSTRACT

There are disclosed esters of retinoic acid and alcohols which are azetidinone derivatives. These esters are useful as anti-cancer agents.

BACKGROUND OF THE INVENTION

This invention relates to esters of retinoic acid and alcohols which are azetidinone derivatives. Such esters are useful as anti-cancer agents.

Retinoic acid, also known as Vitamin A acid, is a well known compound having the formula: ##STR1## Various simple esters of retinoic acid are also known in the art as shown in U.S. Pat. Nos. 2,576,103 and 4,216,224.

Azetidinones have been described in the literature, Just et al (I), Can. J. Chem., 56, pp. 2720-2724 (1978); Just et al (II), Can. J. Chem., 56, pp. 2725-2730 (1978); and Just et al (III), Synth. Comm., 9, pp. 117-121 (1979). Just et al (I) disclose the preparation of compounds having the formula: ##STR2## In Formula I and hereinafter, X is --N₃ or --NHCOCH₂ Ph and Ph is phenyl. The compounds of Formula I may be hydrolyzed to form azetidinone alcohols having the formula: ##STR3## Just et al (II) disclose the preparation of a compound having the formula: ##STR4##

SUMMARY OF THE INVENTION

In accordance with this invention, there are provided retinoic acid esters of the alcohols of Formula II. Such esters have the formulas: ##STR5##

There is also provided the retinoic acid ester of the azetidinone alcohol of Formula III. This ester has the formula: ##STR6##

In accordance with another aspect of this invention, there is provided the retinoic acid ester having the formula: ##STR7##

DETAILED DESCRIPTION OF THE INVENTION

Just et al (III) describe the reaction of a wide range of substituted anilines with a pKa of approximately 2 or higher with cinnamaldehyde to provide a Schiff base. Treatment of the Schiff base with azidoacetyl chloride provides cis-β-lactams exclusively.

As shown in Just et al (I), the compound of Formula I wherein X is --N₃ is obtained as azide 18 (page 2723) which is reduced with hydrogen sulfide/triethylamine to the corresponding amine which is acylated with phenylacetyl chloride to yield amide 19 (page 2723). Treatment of the azide 18 of Just et al (I) with fluoride ion gives the alcohol of Formula III wherein X is --N₃ ; and treatment of the amide 19 of Just et al (I) with fluoride ion gives the alcohol of Formula II wherein X is --NHCOCH₂ Ph.

As shown in Just et al (II), the alcohol of Formula III is obtained by reaction of azide 26 (page 2728) with ozone, followed by sodium borohydride reduction to provide alcohol 27 (page 2728), which upon mesylation gives mesylate 28 (page 2729); mesylate 28 is cyclized to give azide 29a which is reduced with hydrogen sulfide/triethylamine to the corresponding amine which is acylated with phenacetyl chloride to yield amide 29b (page 2729); and amide 29b is treated with trifluoroacetic acid to give the alcohol amide 31 (page 2729).

The following examples are illustrative of the herein claimed invention:

EXAMPLE 1

The compound of Formula III, i.e., alcohol amide 31 of Just et al (II), was transformed to its mesylate as described in Just et al (II) for the conversion of alcohol 27 to mesylate 28 (pages 2728 and 2729). To the mesylate (1 mmol) in 3 ml of dimethyl formamide under a nitrogen atmosphere was added retinoic acid (1 mmol) and potassium carbonate (3 mmol) at room temperature. After 15 hours, ether was added, and the solution washed with water, dried over MgSO₄ and evaporated. Crystallization from pentane gave the desired ester having the structure of Formula VI, mp 85°-88° C.; λ_(max) ^(EtOH) 350 nm (ε 2010); ir V^(CH).sbsp.2^(Cl).sbsp.2 3400, 1770 (β-lactam), 1705 (ester), 1685 cm⁻¹ (amide); m/e (C.I.) 621 (M⁺ +H), nmr 1.02 (s, 6H, 2 CH₃), 1.2-2.4 (m, 15H, 3 CH₃, 3 CH₂), 3.51 (s, 2H, CH₂ --O), 3.79-4.51 (m, 4H, OCH₂ CHCH), 5.31 (s, 2H, OCH₂ Ph), 5.61-6.71 (m, 7H, ═CH and NH), 6.81-7.3 (m, 8H, Ph).

EXAMPLE 2 Step A

The compound of Formula I wherein X is --N₃, i.e., azide 18 of Just et al (I) (page 2723) is converted to the alcohol of Formula II wherein X is --N₃ by the same procedure described in Just et al (I) for the conversion of amide 22 to alcohol 23 (page 2724); i.r. 3500-3300 (OH), 2100 (N₃), 1761 (β-lactam) cm⁻¹.

Step B

The alcohol obtained in Step A was dissolved in methylene chloride. To this solution was added one equivalent of methanesulfonyl chloride and one equivalent of triethylamine at 0° C. The solution was washed with water, dried (MgSO₄) and evaporated to give the mesylate (a compound as defined in Formula I wherein X is --N₃ and the group ##STR8## is replaced with the group OSO₂ CH₃); i.r., 2100 (N₃), 1770 (β-lactam) cm⁻¹ ; n.m.r. δ (ppm), 2.95 (s, 3H, SO₂ CH₃), 5.11 (m, 2H, β-lactam CH--CH), 5.4 (d, 2H, CH₂ O), 6.01-6.98 (m, 2H, CH═CH), 7.39 (m, 9H, aromatic). This mesylate (1 mmol) was stirred in dimethyl formamide (DMF) (3 ml) containing retinoic acid (1 mmol) and K₂ CO₃ (3 mmol) at room temperature for 15 hours. Dilution with water and three extractions with ether, followed by washing with water (3 x) gave, after purification over a charcoal column using diethyl ether as eluent, the retinoate of Formula IV in 90% yield; n.m.r. (CDCl₃) 1.09 (s, 6H, C(CH₃)₂), 1.22-2.45 (m, 15H, 3 CH₃,3 CH₂), 5.00-4.39 (m, 4H, CH₂ and β-lactam CH), 5.80-7.01 (m, 8H, ═CH), 7.41 (m, 9H, Ph); i.r. (CH₂ Cl₂) 1765 (β-lactam), 2100 (N₃), 1710 (ester); u.v. λ_(max) (EtOH) 355 nm (1895); C.I. 603 (M⁺ H).

EXAMPLE 3 Step A

The compound of Formula I wherein X is --NHCOCH₂ Ph, i.e., azide 19 of Just et al (I) (page 2723) is converted to the alcohol of Formula II wherein X is --NHCOCH₂ Ph by the same procedure described in Just et al (I) for the conversion of amide 22 to alcohol 23 (page 2724); i.r. 3480 (OH), 1734 (β-lactam), 1659 (amide) cm⁻¹.

Step B

The alcohol obtained in Step A was dissolved in methylene chloride. To this solution was added one equivalent of methanesulfonyl chloride and one equivalent of triethylamine at 0° C. The solution was washed with water, dried (MgSO₄) and evaporated to give the mesylate (a compound as defined in Formula I wherein X is --NHCOCH₂ Ph and the group ##STR9## is replaced with the group OSO₂ CH₃); n.m.r. (CDCl₃)δ 2.99 (s, 3H, CH₃), 3.60 (s, 2H, CH₂ Ph), 5.1 (bs, 2H, CH₂ OMs), 5.31 (m, 1H, CH β-lactam), 5.4-5.8 (dd, 1H, CHN, J₁ =5 Hz, J₂ =10 Hz), 5.9-6.9 (m, 3H, NH and CH═CH), 7.2-7.4 (m, 14H, Ph); i.r. (CH₂ Cl₂) 3400 (NH), 1770 (β-lactam), 1680 (amide) cm⁻¹. This mesylate was treated with one equivalent of retionic acid (1 mmol) in 3 ml DMF in the presence of three equivalents of K₂ CO₃ which gave, after 15 hours, the retinoate of Formula V which was purified by a short column of charcoal, using ether as eluent; n.m.r. (CDCl₃), 1.01 (S, 6H, C(CH₃)₂), 1.41-2.41 (m, 15H, 3 CH₃ and 3 CH₂), 3.59 (s, 2H, CH₂ CO), 4.51-5.05 (m, 4H, CH₂ O and CHCH), 5.8-6.1 (m, 2H, ═CH, NH), 7.2-7.4 (m, 14H, Ph); i.r. (CH₂ Cl₂), 3400 (NH), 1760 (β-lactam), 1710 (ester) cm⁻¹ ; u.v. λ_(max) (EtOH), 351 nm (1879); C.I. 695 (M⁺ +1).

EXAMPLE 4

The retinoate of Formula VII was prepared according to the following reaction sequence: ##STR10##

α-Pyridoin (2.14 g, 0.01 mol) was dissolved in 20 ml of methylene chloride and triethylamine (1.01 g, 0.01 mol) was added. Then, methanesulfonyl chloride (1.15 g, 0.01 mol) in 9 ml CH₂ Cl₂ was added dropwise at 0° C. After 30 minutes, water was added and the organic layer was washed two times with water, dried, evaporated and purified on silica gel to give a quantitative yield of the mesyl derivative after elution with CHCl₃ ; n.m.r. (CDCl₃) δ3.00 (s, 3H, CH₃), 6.9-8.4 (m, 9H, pyridinic hydrogen and OH). The pyridoin mesylate (1 mmol) was dissolved in DMF (3 ml), and two equivalents of potassium carbonate, followed by 1 mmol of retinoic acid, were added. The solution was stirred under nitrogen for 15 hours at room temperature. Ether was added and the ethereal layer was washed with water (5 times), dried and evaported to give a quantitative yield of the retinoate of Formula VII, which was crystallized from pentane, m.p. 65°-67° C.; n.m.r. (CDCl₃) δ1.01 (s, 6H, C(CH₃), 1.40-2.41 (m, 15H, 3 CH₃ and 3 CH₂), 5.8-6.95 (m, 6H, ═CH), 7.00-8.81 (m, 9H, aromatic pyridine and OH); i.r. (CH₂ Cl₂), 3500 (OH), 1710 (ester), u.v. λ_(max) (EtOH), 355 nm (2212 ); C.I. 497 (M⁺ +1).

The compounds of this invention are useful as anticancer agents--e.g., they exhibit antileukemia activity in laboratory animals.

The biological activities of the retinoic acid esters of this invention were evaluated according to their ability to inhibit squamous metoplasia and keratinization in organ cultures of trachea derived from vitamin A-deficient hamsters according to a procedure described by Sporn et al, Nature, 263, pages 110-113 (1976). The results are set forth in the following table.

                  TABLE                                                            ______________________________________                                                           Reversal of                                                                    Keratinization                                               Retinoid          ED.sub.50.sup.a                                              ______________________________________                                         β-All-trans-retinoic acid                                                                   1.15 × 10.sup.-10 M                                    Compound IV       4.07 × 10.sup.-10 M                                    Compound V        1.98 × 10.sup.-10 M                                    Compound VI       3.90 × 10.sup.-10 M                                    Compound VII      3.10 × 10.sup.-10 M                                    ______________________________________                                          .sup.a Median effective dose (ED.sub.50) for reversal of keratinization i      the dose required for reversal of keratinization of 50% of the explants a      determined by probit analysis.                                            

We claim:
 1. The retinoic acid ester having the formula: ##STR11##
 2. The retinoic acid ester having the formula: ##STR12##
 3. The retinoic acid ester having the formula: ##STR13##
 4. The retinoic acid ester having the formula: ##STR14## 